L13-L14 Epilepsy Flashcards
Compared with the general population, the risk of premature death amongst people with epilepsy is _____.
Increased 2- to 3- fold
Highest w/in 1st 12 months of diagnosis
List all epilepsy-related mortality risk factors.
1) Sudden unexplained death in epilepsy patients (SUDEP)
2) Status epilepticus
3) Unintentional injuries (e.g. drowning, head injuries, burns) during episodes
4) Suicide
Explain what “SUDEP” means.
Sudden unexplained death in epilepsy patients
1) Incidence: 1-2 per 1000 person-years
- Peak: 20-40 y/o
2) Mostly unwitnessed and sleep-related
- Many individuals w/ SUDEP are found in prone position w/ evidence of having had a recent seizure.
- Rare cases occurring during video electroencephalogram (EEG) monitoring suggests that SUDEP is preceded by a convulsion followed shortly w/ apnoea (i.e. cessation of breathing) then asystole (i.e. cessation of electrical & mechanical activity of the heart)
What are some risk factors that may lead to the occurrence of SUDEP in epileptic patients?
1) Presence & frequency of generalised tonic-clonic seizures
2) Nocturnal seizures
3) Lack of seizure freedom
Based on the ILAE guidelines, differentiate between seizure and epilepsy.
Seizure:
Transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain
Epilepsy:
Disease of the brain defined by ANY of the following conditions:
1) At least 2 unprovoked seizures occurring > 24h apart
2) One unprovoked seizure AND a probability of further seizures similar to general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years
3) Diagnosis of an epilepsy syndrome
- Conceptually, epilepsy is a brain disorder characterised by an enduring predisposition to generate epileptic seizures.
What are some differential factors that help distinguish if a seizure is provoked or unprovoked?
STIIM:
- Interval between insult & seizure may vary according to the underlying condition.
1) Structural: Traumatic brain injury & stroke (scar formation in brain)
2) Toxic substance/drugs:
- Illicit drugs (e.g. cocaine, amphetamines)
- Drugs (e.g. TCAs, carbapenems)
- Alcohol withdrawal & intoxication
- BZDs (abrupt) withdrawal
3) Infections:
4) Inflammation
- CNS infection (e.g. neurosyphillis, meningitis, enchepalitis)
- Febrile illlnesses
5) Metabolic (including electrolyte imbalances):
- Hyponatremia
- Hypokalemia
- Hypomagnesemia
- Hypoglycemia
Explain the pathophysiology leading to a seizure episode.
Key Concepts: Hyperexcitability & Hypersynchronisation
- Instability in a single neuronal cell membrane or group of cells around it
- Characterised by synchronised paroxysmal discharges occurring in a large population of neurons w/in cortex.
1) Hyperexcitability: Enhanced predisposition of a neuron to depolarise due to…
- Abnormalities in Na+, K+, Ca2+ and Cl- ions in ICF & ECF across voltage-gated Na+, K+, Ca2+ and Cl- ion channels
- Excessive excitatory neurotransmitters (e.g. glutamine, acetylcholine, histamines, cytokines etc.)
- Insufficient inhibitory neurotransmitters (e.g. GABA, dopamine)
2) Hypersnychronisation:
- Intrinsic organisation of local circuits (i.e. hippocampus, neocortex & thalamus) contribute to synchronisation and promote generation of epileptiform activity.
List the various etiologies of epilepsy.
1) Genetic
2) Structural: Traumatic brain injury, tumours, hypoxic-ischemic abnormalities, vascular malformation
3) Metabolic: Mitochondrial disorders, glucose transporter 1 (GLUT1) deficiency
4) Immune: Ab mediated
5) Infection: Bacterial meningitis, HIV, meningo-TB
6) Unknown
Explain how the various types of epilepsy are classified.
Based on mode of onset:
1) Focal onset: Seizures ONLY in one hemisphere
- May spread to contralateral hemisphere i.e. focal seizures evolving to bilateral convulsive seizures
2) Generalised onset: Seizures begin in BOTH hemispheres
AND Based on impairment of consciousness:
- Loss of awareness of external stimuli or inability to respond to external stimuli in a purposeful & appropriate manner
- Described as “with or without dyscognitive features”
What significance does the classification of seizures under ILAE guidelines have in the Tx of epilepsy?
Fundamental characteristic by which to classify seizures helps in identifying treatment & prognostic implications.
Based on the ILAE 2017 Classification of Seizure Types, what key features were used as basis of classifying the various types of epilepsy?
Based on THREE key features:
1) Mode of onset / where seizures begin in the brain
2) Level of awareness during seizure episodes
3) Other features of seizures
Redefine “simple partial seizures” appropriately using the updated terminology in ILAE.
Focal onset seizures without dyscognitive features
Redefine “complex partial seizures” appropriately using the updated terminology in ILAE.
Focal onset seizures with dyscognitive features
What are the factors affecting the clinical characteristics of a seizure?
1) Site of focus
2) Degree of ‘irritability’ of the areas of the brain surrounding the focus
3) Intensity of impulse
Describe the typical clinical presentation of a patient diagnosed with a FOCAL onset seizure WITHOUT dyscognitive features.
1) Motor Symptoms:
- Clonic (i.e. twitching or jerking) movements of the arm, shoulders, face & leg
- Speech arrest / Dysartharia (i.e. involving muscles of articulation)
2) Sensory Symptoms:
- Tingling or feelings of numbness
- Visual disturbances (e.g. flashing lights)
- Rising epigastric sensation
3) Autonomic Symptoms:
- Sweating, salivation or pallor
- Increased BP & HR
4) Somatosensory / Psychic Symptoms:
- Flashbacks, deja vu memories
- Visual, auditory, olfactory & gustatory hallucinations
- Affective symptoms include fear (most common), depression, anger & irritability
Describe the typical clinical presentation of a patient diagnosed with a FOCAL onset seizure WITH dyscognitive features.
1) Aura / Somatosensory / Psychic Symptoms:
- Manifestations as described in focal non-dyscognitive features seizures
- Usually last for a few seconds
- i.e. Flashbacks, deja vu memories
- Visual, auditory, olfactory & gustatory hallucinations
- Affective symptoms include fear (most common), depression, anger & irritability
2) Impaired consciousness: Amnesia to event
3) Automatisms: Lip smacking, chewing, repetitive speech, picking at their clothes unpurposefully
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset tonic-clonic seizure.
Most common & best known type; also known as “grand mal”.
Begins w/ stiffening of limbs (tonic phase), followed by jerking of limbs and face (clonic phase)
1) Tonic Phase:
- Begins w/ stiffening of limbs
- Breathing may decrease or cease altogether
- Cyanosis of nail beds, lips & face
2) Clonic Phase:
- Followed by jerking of limbs & face after tonic phase
- Reversal of cyanosis typically in clonic phase but may be irregular
- Usually lasts for 1 min, after which brain is extremely hyperpolarised & insensitive to stimuli
- Incontinence may occur, along with biting of tongue or inside of mouth
- Breathing may be noisy & appeared to be laboured
3) Post-Seizure:
- Following seizure episode, pt may have HA & appeared lethargic, confused & sleepy
- Full recovery takes several minutes to hours
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset clonic seizure.
Clonic jerking often asymmetrical & irregular
Clonic seizures are most frequent in neonates, infants or young children.
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset tonic seizure.
Sudden loss of consciousness & rigid posture of entire body that last 10-20 seconds
- Occur at all ages in setting of diffuse cerebral damage & learning disability
- Invariably associated with other seizure types
- Characteristics & defining seizure type in Lennox-Gastaut syndrome
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset absence seizure.
Known as “petit mal” seizures in literature.
1) Usually manifests as basic lapse in awareness that begins & ends abruptly.
- Sometimes mistaken as persistent staring
- Lasts ONLY a few seconds W/O warning W/O after-effects
- Often undetected even if there are 50-100 attacks/day
2) 1st onset: Usually 4-12 y/o; rarely after 20 y/o
- More common in children than in adults
3) Absence seizures DIFFER from complex partial seizures in that they:
- NEVER preceded by auras
- last SECONDS (rather than minutes)
- begin FREQUENTLY & end ABRUPTLY
- produce CHARACTERISTIC EEG pattern “3Hz spike waves”
- May be mistaken for complex partial seizures, resulting in wrong choice of medication prescribed.
Describe the typical clinical presentation of a patient diagnosed with a GENERALISED onset atonic seizure.
Most SEVERE form is the classic drop attack (astatic seizure) in which all postural tone is suddenly lost, causing collapse to the ground like a rag doll
- Short episode & followed by immediate recovery
- Occur at any age & are always associated w/ diffuse cerebral damage & learning disability
- Common in severe symptomatic epilepsies (esp. in Lennox-Gastaut syndrome & in myoclonic-astatic epilepsy)
What are the laboratory tests and investigations that are used in the diagnosis and management of seizures?
1) Thorough Hx-taking is impt.:
- Description of onset, duration & characteristics of a seizure
- Accurate Hx best provided by person who has observed events
- Pt. is useful in describing details of auras, preservation of consciousness & post-ictal/post-seizure state
2) Neurological examinations:
- Scalp electroencephalography (EEG)
- Video EEG
- Magnetic resonance imaging (MRI) w/ gadolinium
3) Biochemical / Toxicology lab exams
4) Concomitant medical conditions
What are some classical characteristics that positively identifies a patient experiencing symptoms of epilepsy?
- Aura
- Cyanosis
- Loss of consciousness
- Motor manifestations
- Generalised stiffness of limbs & body
- Jerking of limbs
- Tongue biting
- Urinary incontinence
- Post-ictal/seizure confusion
- Muscle soreness
What are some differential diagnoses to exclude before identifying one has epilepsy?
Syncope: “fit” (seizures) vs “faint” (syncope) dilemma
Transient ischaemic attack
Migraine
Psychogenic nonepileptic seizures
Describe how the scalp EEG helps in the diagnosis of epilepsy.
Essential tool for diagnosis & classification of seizures & epileptic syndromes
- Epileptiform discharges on EEG CONFIRM diagnosis
- However, a normal EEG does NOT exclude possibility of epilepsy
What are the limitations of using scalp EEG to help in the diagnosis of epilepsy?
1) NOT all epileptic patients have an abnormal EEG.
- 50% chance of showing epileptiform activity in a first awake EEG.
- 80-90% sensitivity w/ repeated awake-sleep EEGs.
2) EEG can be abnormal in normal persons
- False-positive epileptiform discharges on EEG in asymptomatic adults = 0.5-1%
Describe how the video EEG helps in the diagnosis of epilepsy.
Increasingly being used in diagnosis in pt w/ suspected psychogenic non-epileptic seizures (PNES)
If matching epileptic EEG w/ actual video evidence shows manifestations of seizure event, it is a good indicator to diagnose if indeed is an unprovoked seizure.
Describe how the MRI w/ gadolinium helps in the diagnosis of epilepsy.
Ordered for adult pt who presents w/ 1st seizures, pt w/ focal neurological deficits or suggestion of focal onset seizure.
Helps in the identification of focal lesions:
- Mesial temporal sclerosis
- Focal cortical dysplasia
- Remote injury (old stroke etc)
- Tumor
- Vascular malformation
Describe how the biochemical / toxicology investigations help in the diagnosis of epilepsy.
Helps to rule out electrolyte abnormalities
Creatinine kinase is usually raised after generalised tonic-clonic seizure episode.
Serum prolactin can be used routinely as a biochemical marker to diagnose patients with epilepsy. True or false?
False.
Considerable variability & NOT used routinely.
Describe the algorithm in determining whether a patient has epilepsy upon first seizure.
1) Was it a seizure?
2) Was it the first seizure?
3) Was it a provoked seizure?
4) If not, what is the likely etiology?
5) Does the patient need anti-seizure medications (ASM)?
- What is the risk of seizure recurrence?
- Patient factors
- Which ASM?
How do we determine the risk of seizure recurrence?
1) Risk of second seizure:
- ~30% w/in next 5 years, higher in first 2 years
- Higher in presence of:
(a) Epileptiform EEG
(b) Prior brain insult (i.e. stroke, trauma)
(c) Structural abnormality in brain imaging
(d) Noctural seizure
2) Risk of recurrent seizures after two unprovoked seizures at 4 years = 70%
What are some considerations before starting on ASM?
Considerations:
1) Recurrence risk:
- Treatment after 1st seizure can reduce risk of 2nd seizure
- However, no effect on long-term prognosis.
- No evidence of higher risk of death, injuries or status epilepticus in pt allocated to deferred Tx in FIRST & MESS studies
2) Potential seizure morbidity
3) Risk of Tx
4) Personal circumstances
Key Determinants:
1) Cause, epilepsy syndrome, EEG findings
2) Seizure types
3) Tolerability
4) Work, need for drive license, desire to bear children
DO NOT START Tx when pt isn’t at high risk (i.e. > 60%)!!
What are the therapeutic goals in the treatment of epilepsy?
1) Absence of epileptic seizures
2) Absence of ASM-related side effects
3) Attainment of optimal QoL
About 2/3 of pt are able to achieve seizure freedom.
Non-pharmacological options are the mainstay in the Tx of epilepsy. True or false?
False.
Pharmacological Tx is the mainstay, while non-pharmacological options are adjunctive.
What are some non-pharmacological options a pt w/ epilepsy may consider adopting?
1) Ketogenic diet
2) Lifestyle modifications: Seizure diary & avoid preventable seizure triggers where possible
3) Vagus nerve stimulation (VNS)
4) Responsive neurostimulator system (RNS)
5) Surgery
Treatment strategy for epilepsy should be individualised according to:
1) Seizure type and/or epilepsy syndrome:
- Whether rapid titration is required
- E.g. lamotrigine & topiramate requires slow titration; carbamezapine undergoes autoinduction
2) Co-medications & comorbidities:
- Migraine: Consider topiramate, valproate
- Depression/Anxiety: Use levetiracetam w/ caution
- DDI: Caution for pt on HIV medications & immunosuppressants
- Route of elimination i.e. Hepatic / renal impairment
- Special population: Consider levetiracetam / lamotrigine & AVOID valproate for women w/ childbearing potential
3) Pt’s lifestyle & preferences:
- Dosage form & dosing frequency
- Lifestyle & occupational considerations
4) National / Institutional:
- Guidelines
- Availability
- Costs & financial subsidies
What are the general principles driving the selection of pharmacological treatment of epilepsy?
1) Monotherapy preferred:
- Likely lower incidence of adverse effect
- Absence of DDI
- Reduced risk of birth defects
- Lower cost
- Easier to correlate response & adverse effects
- Better adherence
2) Tx Initiation: Start w/ low dose of 1st line ASM appropriate for particular seizure type
- If seizures continue BUT no side effects, gradually increase dose of ASM
- If seizures continue despite maximum tolerated dose of 1st line ASM:
(a) Review diagnosis
(b) Ensure appropriate drug for seizure type / epileptic syndrome
(c) Check adherence
3) Failure of 1st line Tx of ASM:
- Chances of seizure freedom after failure of 1st ASM is low = 16%; may require combination (adjunctive) Tx
- No consensus / sufficient evidence / validated algorithm to support substitution monotherapy or combination Tx
- Substitution: Consider if 1st ASM produces ADR & not tolerated at low doses / does not improve seizures
- Combination Tx: Consider if pt tolerates 1st or 2nd ASM BUT w/ suboptimal response
What are some factors to consider when combining ASMs for pharmacological Tx of epilepsy after the failure of 1st line ASM?
1) Previous clinical response of patient to each drug alone
2) ASM’s MOA
3) ASM’s tolerability profile
4) ASM’s PK profile
About _____ of patients w/ new onset focal or generalised seizures achieve _____ while taking the ______ 1st line antiepileptic drug.
50%
Seizure freedom
Initial appropriately selected & dosed
About _____ of patients have drug resistant epilepsy, which is defined as failure of adequate trials of _____, _____ & _____ to achieve sustained seizure freedom.
30%
TWO tolerated, appropriately chosen & used antiepileptic drug schedule
Describe how the ketogenic diet is used as a non-pharmacological Tx option for epileptic patients.
1) Used in patients who cannot tolerate or have NOT responded well to ASM treatment.
- Used mainly in young children (evidence) to prevent seizures
2) Comprises of low carbohydrate, high-fat diet to induce ketosis.
- Aim to change how the brain uses energy (from carbohydrates to ketones) to function, though MOA is not well understood.
- Challenging to adhere long-term
Describe how the vagus nerve stimulation is used as a non-pharmacological Tx option for epileptic patients.
Indicated ONLY for intractable focal seizures
- Electrodes attached around left branch of vagus nerve as well as well as connected to programmable stimulator
- Stimulator delivers cyclical stimulation
- During a seizure, ‘on-demand’ stimulation can be achieved by placing a magnet next to SC-implanted stimulator
Describe how the responsive neurostimulator system is used as a non-pharmacological Tx option for epileptic patients.
New adjunctive therapy to help reduce the frequency of partial-onset seizures in pt who have:
- Undergone diagnostic testing that localised at most TWO epileptogenic foci
- Refractory to at least TWO ASMs
- Frequent & disabling symptoms
RNS continuously monitors electrical activity in the brain, detects patient-specific patterns & delivers brief pulses of stimulation when it detects activity that could lead to a seizure.
Describe how surgery is used as a non-pharmacological Tx option for epileptic patients.
May be useful in up to 90% w/ selected forms of epilepsy to achieve improvement of symptoms or seizure-free status.
Usually advocated as early therapy for SPECIFIC epileptic syndromes:
- e.g. temporal lobe epilepsy w/ or w/o mesial temporal sclerosis
- e.g. frontal lobe epilepsy w/ or w/o identifiable lesion on MRI scan
- Last option vs continued drug Tx for certain refractory cases
What are the psychosocial issues epileptic patients face in reality?
1) Social stigma (e.g. marriage, starting a family)
2) Employment:
- Require more time away from work for medical follow-up
- Higher medical costs borned by employer
3) Prohibited from driving, depending on country / state
- Prohibited in SG regardless of whether seizure-free for > 2 years
4) Caregiver burden
Physical & psychiatric comorbidities in epileptic patients are associated with _____, _____, _____ & _____.
1) Poorer health outcomes
2) Increased healthcare needs
3) Decreased QoL
4) Greater social exclusion
What are the most common psychiatric comorbidities in adult epileptic patients?
Depression (23%) & anxiety (20%)
What are the most common psychiatric comorbidities in children with epilepsy?
Intellectual disability (30-40%)
What are some recommendations we can provide to epileptic patients as part of patient education?
1) Avoiding preventable known seizure triggers:
- Hyperventilation
- Photostimulation
- Physical & emotional stress
- Sleep deprivation
- Electrolyte imbalance: Hypoglycemia, hypo/hypernatremia, hypocalcemia, hypomagnesemia
- Sensory stimuli
- Infection
- Hormonal changes (time of menses, puberty or pregnancy)
- Drugs: Theophylline, alcohol, high-dose FGA, antidepressants (esp. bupropion), tramadol & carbapenems
2) Awareness to ASM potential side effects & DDI
- E.g. warfarin
3) Avoid / seek exemption from high-risk activities such as driving, firearms (in NS) & swimming
4) Recommend community resources to refer to
5) Practise habit to journal in seizure diary.
What information does the seizure diary provide to help with monitoring epilepsy management outside of primary healthcare?
Seizure frequency & types How long they last Changes in ASMs ASM side effects Seizure triggers
Name some appropriate seizure first-aid procedures you can do in the event of a patient experiencing a generalised tonic-clonic seizure episode.
1) Ease the person on the floor
2) Turn the person gently onto one side to help him/her breathe.
3) Clear the area around person from anything sharp or hard to prevent injuries.
4) Put something soft & flat, like a folded jacket under person’s head
5) Remove eyeglasses
6) Loosen ties or anything around neck that make it hard for the person to breathe
* 7) Time the seizure. Call 995 if seizure last > 5 min (ie. status epilepticus)
Name some INAPPROPRIATE seizure first-aid procedures you should AVOID in the event of a patient experiencing a generalised tonic-clonic seizure episode.
DON’T:
1) Hold person down or stop movements.
2) Put anything in the mouth - brings injury to teeth or jaw, as person cannot swallow his/her tongue during seizure
3) Give mouth-to-mouth resuscitation.
4) Offer water or food until person is fully alert.
List the first-line ASMs available for new onset of focal onset epilepsy.
Carbamazepine (ILAE Level A) Levetiracetam (ILAE Level A) Phenytoin (ILAE Level A) Valproate (ILAE Level B) Topiramate (ILAE Level C)
Esp. for elderly:
Lamotrigine (ILAE Level A)
Gabapentin (ILAE Level A)
NOT available in SG:
Oxcarbazepine
Zonisamide (ILAE Level A)
List the first-line ASMs available for new onset of generalised onset epilepsy.
Lamotrigine (ILAE Level C)
Valproate (ILAE Level C)
Carbamazepine (ILAE Level C)
Topiramate (ILAE Level C)
List the ASMs available for refractory focal onset epilepsy.
Clobazem
Lacosamide
Pregabalin (good for elderly)
Perampanel
List the ASMs available for refractory generalised onset epilepsy.
Clobazem
Levetiracetam
Which ASM should be used with caution or avoided when an epileptic patient has MDD as comorbidity?
Levetiracetam
Which ASM should be used with caution or avoided when an epileptic patient has GAD as comorbidity?
Levetiracetam
Which ASM should be avoided in an epileptic woman with childbearing potential?
Which ASMs can be considered instead?
Valproate, due to teratogenicity issues esp. in 1st semester
Levetiracetam / Lamotrigine
Which ASMs can be considered in an epileptic patient who presents with an accompanying migraine?
Topiramate / Valproate
List all clinically used first-generation ASMs.
1st-line:
Carbamazepine
Valproate
Phenytoin
2nd-line:
Phenobarbital/ Phenobarbitone
List all clinically used second-generation ASMs.
1st-line:
Lamotrigine (helpful for mood disorder, bipolar disorder)
Levetiracetam
Topiramate
2nd-line:
Gabapentin (helpful for neuropathic pain)
Pregabalin (helpful for neuropathic pain)
What are the usual maintenance doses for commonly used ASMs?
Phenytoin: 300 – 400 mg/day (5 – 7 mg/kg/day)
Valproate: 600 – 2000 mg/day (20 – 30 mg/kg/day, max 60 mg/kg/day)
Carbamazepine: 800 – 1200 mg/day
Phenobarbital: 60 – 180 mg/day
Lamotrigine: 100 – 200 mg/day
Topiramate: 200 – 400 mg/day
Levetiracetam: 1000 – 3000 mg/day
What are some pharmacokinetic issues with respect to the administration of 1st-gen ASM?
1) Poor water solubility
2) Extensive plasma protein binding
- Significant in hypoalbuminemia where higher % free drug does NOT mean greater clinical effect
- Valproate exhibits saturable plasma protein binding (i.e. non-linear PK)
3) Extensive oxidative metabolism
- Carbamazepine undergoes autoinduction (i.e. time-dependent PK)
- Phenytoin undergoes saturable oxidative metabolism (i.e. non-linear PK)
4) Vulnerable to multiple DDIs
What are some potential pharmacokinetic advantages of administering 2nd-gen ASM over 1st-gen ASM?
1) Improved water solubility allows for more predictable F
2) Negligible protein binding (generally), thus not concerned over hypoalbuminemia
3) Less reliance on CYP metabolism for elimination
- BUT more vulnerable to renal dose adjustment (i.e. CKD)
4) Less vulnerable to DDI
Which key targets are prone to DDI with co-administration with ASMs?
CYP450
UGT
Transporters
Which first-generation ASMs are potent enzyme inducers?
Carbamazepine: CYP (1A2, 2C, 3A4) & UGTs
Phenytoin: CYP (2C, 3A) & UGTs
Phenobarbital: CYP (1A, 2A6, 2B, 3A) & UGTs
Which first-generation ASMs are potent enzyme inhibitors?
Valproate: CYP2C9 & UGT
Which second-generation ASM is a moderate CYP3A inducer?
Topiramate
Which second-generation ASMs are not susceptible to potential DDI?
Gabapentin, levetiracetam, pregabalin
Which second-generation ASM is a moderate CYP2C19 inhibitor?
Topiramate
What type of interactions is not captured by most pharmacy technological systems in SG & may be easily overlooked?
1) De-induction interactions
- When enzyme-inducing ASM is discontinued, the activity of affected enzymes return to baseline.
- Drugs that are metabolised by affected enzymes may require dose adjustment.
2) De-inhibition interactions
- Similar conceptual understanding (e.g. valproate discontinuation) to dose adjust accordingly due to current overdosage upon removal of valproate
What are some issues associated w/ the use of enzyme-inducing ASMs?
1) Women: Dysregulation of reproductive hormones, changes in sexual function & use of oral contraceptives
2) Changes in sexual function & fertility in men
3) Bone health: Osteopenia & osteomalacia esp. in elderly!
4) Vascular risk (esp. statins)
5) Multiple DDIs
What are some drug classes that are potentially affected by enzyme-inducing ASMs?
1) Opioid analgesics
2) Antidepressants
3) Antipsychotics
4) Antiretrovirals
5) Antimicrobials (azoles)
6) BZDs
7) Chemotherapeutic agents
8) CCBs
9) Antiarrhythmics
10) Corticosteroids
11) Statins / HMG-CoA inhibitors
12) Immunosuppressants
13) Warfarin
14) Oral contraceptives
The bioavailability of phenytoin is _____, but its rate of absorption is _____. Thus, F is _____ at lower dose > 400mcg/dose due to _____. Moreover, F is _____ by NGT and feeds interaction, and administration of phenytoin should be _____.
F = 1 Slow Saturable absorption Reduced Spaced 1-2h apart between feeds and dosing.
Phenytoin is _____, resulting in an average Vd of _____ L/kg. Thus, hypoalbuminemia will _____ free phenytoin in plasma & should be corrected when albumin ____ g/L.
C(corrected) = C(observed) / [x.(Alb/10) + 0.1] x = 0.2 when CrCL \_\_\_\_\_ mL/min x = 0.1 when CrCL \_\_\_\_\_ mL/min Albumin in g/L C in mg/L
Highly plasma protein (albumin) bound (~90%)
0.7 L/kg
Increase
< 40 g/L
x = 0.2 when CrCL >= 10 mL/min x = 0.1 when CrCL < 10 mL/min
What conditions can the plasma protein binding of phenytoin to albumin be altered?
1) Presence of other highly plasma protein-bound drugs via displacement.
- e.g. warfarin, NSAIDs including high-dose aspirin & valproate
2) Uremia
Phenytoin exhibits saturable / capacity-limited ____, where increasing concentrations of phenytoin will _____. Thus, concentration increment is _____ to dose increment of phenytoin.
Saturable metabolism / clearance
Decrease clearance
NOT proportional (i.e. zero-order kinetics)
Which of the first-generation ASM do NOT have IV or syrup formulations, unlike the others within the generation?
Carbamazepine
- Both valproate & phenytoin have IV, PO tablets & syrup formulations available in the market.
The bioavailability of valproate is _____, and is _____, resulting in small Vd. Valproate experiences saturable ____ within the therapeutic range, where increasing concentrations will ____ protein binding. Thus, hypoalbuminemia will _____ free valproate in plasma.
Close to 1 (F = 1) Highly plasma protein (albumin) bound (~90-95%) Saturable plasma protein binding Decrease Increase fu (since Cu increases)
What conditions can the plasma protein binding of valproate to albumin be altered?
1) Presence of other highly plasma protein-bound drugs via displacement.
- e.g. warfarin, NSAIDs including high-dose aspirin & phenytoin
2) Uremia
3) Hyperbilirubinemia
As valproate experiences saturable plasma protein binding, the total valproic acid concentrations increase in a ______ fashion as dosage increases. However, free valproic acid concentrations will increase in a _____ fashion with dosage increment. Thus, it is vital to interpret the correct valproate levels for patients with _____.
Non-linear
Linear
Hypoalbuminemia
The bioavailability of carbamazepine is _____, and is _____, but has a large Vd of _____ L/kg. Carbamazepine experiences _____ within the therapeutic range, where its clearance ____ over time, resulting in a _____ T1/2 over time.
0.8
Highly plasma protein (i.e. BOTH alpha-1-acid glycoprotein & albumin) bound (75-80%)
1.4 L/kg
Autoinduction of CYP3A4 oxidative metabolism (>99%)
Increasing
Shorter
What is the implication of the autoinduction of CYP3A4 by carbamazepine on its dosing administration?
Do NOT start w/ desired maintenance dose at first dose, BUT gradually increase over initial few weeks.
- Maximal autoinduction usually occurs 2-3 weeks after dose initiation
- Carbamazepine concentration will decline & stabilise in accordance with the new clearance half-life after steady-state is achieved.
Briefly describe some potential adverse effects upon the administration of ASMs.
1) Dose- / Plasma concentration-dependent ADR
- Usually the main limiting factor in Tx of epilepsy
- Severity & frequency vary amongst ASMs
- More frequent & occur at lower PDC in combination ASM Tx, influenced by additive neurological effects, particularly during initiation BUT may disappear as tolerance develops
- May be avoided or minimised by appropriate preventive measures
2) Idiopathic / Hypersensitivity ADR
- Most likely to occur in the first few months of Tx
3) Chronic systemic ADR
- Tends to be drug-specific & dose-independent
- Usually NOT life-threatening BUT may impact on pt’s QoL
- May be avoided or minimised by appropriate preventive measures
List the dose-dependent adverse effects of ASMs.
More prominent at higher ASM concentrations:
1) CNS: Somnolence, fatigue, dizziness, visual disturbances (usually double/blurred vision), nystagmus, ataxia
2) GI: N/V (specific to carbamazepine & valproate)
3) Psychiatric: Behavioural disturbances (levetiracetam)
4) Cognition: usually sleep fluency (topiramate)
How can the occurrence & severity of dose-dependent adverse effects be minimised?
1) Initiate Tx at a low dose & slowly increasing the dose
2) Avoiding large dosage changes
3) Restricting Tx to one ASM only, if clinically feasible
4) Adjusting the administration schedule
- Administer the largest dose at bedtime
- Dividing a daily dose into smaller doses given more frequently
- Use of sustained-release formulations (reduced peak conc.)
- Reducing the total daily dose (if clinically safe)
List the idiosyncratic adverse effects of ASMs.
All current ASMs (except some 2nd-gen ASMs) have been associated w/the development of rare BUT serious hypersensitivity reactions:
- Blood dyscrasia (Aplastic anemia, agranulocytosis)
- Hepatotoxicity (esp. 1st-gen ASM: valproate, carbamazepine & phenytoin)
- Pancreatitis (esp. valproate)
- Lupus-like reaction
- Exfoliative dermatitis
- Stevens-Johnson syndrome (< 10% BSA) / toxic epidermal necrolysis (>30% of BSA) (SJS/TEN)
- Anticonvulsant hypersensitivity syndrome (AHS)
What are some systemic side effects resulting from chronic administration of ASMs?
1) Connective tissues:
- Gingival hyperplasia (phenytoin)
- Hirsutism in children & young adults, up to 30% of young females (phenytoin)
- Alopecia (valproate)
2) Neurological:
- Encephalopathy (high-dose phenytoin & phenobarbital)
- Peripheral neuropathy, such as sensory loss (valproate, carbamazepine & phenobarbital) -> May respond with folate supplementation; may or may not improve with a decrease in ASM
3) GI:
- Increased weight gain (valproate) -> Gradually reverses spontaneously w/ discontinuation of Tx
- Anorexia & weight loss (topiramate) -> Reversible w/ discontinuation of Tx
4) Endocrine:
- Osteomalacia (phenytoin, phenobarbital & carbamazepine i.e. inducers) is often attributed to increased Cl of Vit D, leading to 2o hyperparathyroidism, increased bone turnover & reduced bone density
- Valproate is also reported to result in osteomalacia via direct CYP inhibition on Vit D pathway.
5) Hematological:
- Blood dyscrasia: Isolated cases associated w/ nearly ALL ASMs
- (rare < 1%) Megaloblastic anaemia (phenytoin predominantly > carbamazepine & phenobarbital)
6) Neonatal congenital effects
- Associated w/ phenytoin, phenobarbital, topiramate & valproate (cognition)
7) Suicidal ideation
- No change to ongoing Tx w/o first discussing w/ physician
- Closer monitoring of symptoms required
What are some risk management strategies done clinically to minimise the risk of hypersensitivity reactions as a result of administering ASMs?
1) PGx testing of HLA-B1502 before starting carbamazepine (mandatory from HSA) & phenytoin
- Esp. for Han Chinese & other Asian ethnic groups (e.g. Malays, Indians, Thais)
- HLA-B1502 positive: AVOID carbamazepine & phenytoin
2) Follow dosing guidance for lamotrigine
- Risk of serious cutaneous reaction is higher in high starting dose, rapid dose escalation & concomitant valproate
- Recommended to do slow dose titration from initial dose
3) Identification of potential cross-sensitivity reaction between aromatic ASMs
- i.e. carbamazepine, phenytoin, phenobarbital, lamotrigine & oxcarbazepine
- Main hypothesis is aromatic ring can form arene-oxide reactive intermediate & become immunogenic upon covalent binding w/ proteins or cellular macromolecules
Which first-line ASMs do NOT have aromatic rings, thus having less risk of causing hypersensitivity reactions?
Valproate, levetiracetam, gabapentin, topiramate
Which first-line ASMs are attributed to have a higher risk of causing hypersensitivity reactions?
Aromatic ASMs:
Carbamazepine, phenytoin, phenobarbital, lamotrigine
What are some side effects of carbamazepine?
Common (conc.-dependent):
Nystagmus, N/V, lethargy, dizziness, drowsiness, headache, blurred vision, diplopia, unsteadiness, ataxia, incoordination
Less common:
Hyponatremia, leukopenia, aplastic anemia, rash, SJS, hepatotoxicity, osteopenia/osteoporosis, neuropathy
What are some side effects of phenytoin?
Common:
Nystagmus, N/V, lethargy, dizziness, drowsiness, headache, blurred vision, diplopia, unsteadiness, ataxia, incoordination
Less common:
Gum hypertrophy, hirsutism, neuropathy, dyskinesia, macrocytic anemia, blood dyscrasis, osteoporosis, hepatotoxicity, rash, SJS/TEN
What are some side effects of valproate?
Common:
N/V, weight gain, ataxia, tremor
Less common:
Hepatotoxicity, thrombocytopenia, pancreatitis, alopecia, hyperammonemia
What are some side effects of phenobarbital?
Common: Sedation and drowsiness
Less common: Dysarthria, ataxia, incoordination, nystagmus
What are some side effects of levetiracetam?
Common:
Somnolence, dizziness, asthenia, coordination difficulties (especially first 4 weeks of initiation), headache
Less common:
Irritability & aggression
What are some side effects of lamotrigine?
Common:
Dizziness, N/V, headache, incoordination, tremor, somnolence, asthenia, headache
Less common:
Rash, SJS/TEN
What are some side effects of topiramate?
Common:
Somnolence, ataxia, fatigue, cognitive dysfunction (psychomotor slowing, speech, memory), weight loss, N/V
Less common:
Glaucoma, hyperammonemia, metabolic acidosis, hyperthermia (oligohidrosis), paresthesias, renal stones
What are some side effects of pregabalin & gabapentin?
Common: Drowsiness, ataxia, weight gain, dizziness
Less common: Peripheral edema
Discuss what the appropriate indications for TDM of ASMs are.
1) To establish an individual’s therapeutic range
- Reference range – may not be effective for all
- Document “effective” level for individual which controls seizures while minimizing side effects once stable
- Helps in subsequent dose changes due to PK changes, DDI, conditions
2) To assess lack of efficacy due to:
- Fast metabolizers?
- Compliance/Adherence issues?
- Other problems?
- Aid in deciding when to change drugs vs need to rework-up diagnosis i.e. right drug for the right disease
3) To assess potential toxicity due to:
- Changing physiology?
- Slow metabolizers?
- Concomitant disease/drugs?
• Renal (uremia, hypoalbuminemia)
• Liver (CYP enzymes)
• New drugs/interactions
- Concentration-dependent adverse effects?
4) To assess loss of efficacy (i.e. breakthrough seizures) due to:
- Changes in physiology (age, pregnancy)
- Changes in pathology
- Changed formulation (brand vs generic, dosage forms)
- DDI
What information is required before conducting therapeutic drug monitoring in patients taking ASM?
1) Indication of ASM (i.e. diagnosis)
2) Dose, dosing freq. & Tx duration of ASM
3) Sample: Time taken & sample type
4) Clinical condition: Seizure control at baseline vs currently & comorbidities
5) Other pertinent lab values
6) Concomitant drug administration (including dose, dosing freq. & Tx duration)
List the TDM reference ranges of 1st-gen ASMs.
Phenytoin: 10 – 20 mg/L
Valproate: 50 – 100 mg/L
Carbamazepine: 4 – 12 mg/L
Phenobarbital: 15 – 40 mg/L
What counselling points should be given to women of childbearing age before starting on ASM for epilepsy?
Before pregnancy:
1) Receive counselling on importance of early discussion on family planning
2) Potential risk to fetus – uncontrolled seizures and teratogenic potential of ASMs
3) Limited efficacy of oral contraceptives (OCs)
- Potent enzyme inducers (i.e. 1st-gen ASM except valproate) may render OCs ineffective; alternative methods required (i.e. barrier methods)
- For patients on lamotrigine, OC may lower lamotrigine concentrations, resulting in breakthrough seizures
After pregnancy:
1) Women with epilepsy should be referred to specialist care for pre-conception counseling
2) Taking ASMs is not an absolute contraindication to breastfeeding
3) All breastfeeding women on ASM therapy should be encouraged to breastfeed
4) Should be encouraged to receive support from relevant healthcare professionals
Describe the clinical definition of status epilepticus.
Status epilepticus is a condition resulting:
1) either from the failure of mechanisms responsible for seizure termination
2) or from the initiation of mechanisms which lead to abnormally prolonged seizures (T1).
It is a condition that can have long-term consequences (T2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.
When is a generalised tonic-clonic seizure is likely to be prolonged, leading to a continuous seizure activity?
T1 = 5 min
When is a generalised tonic-clonic seizure is likely to cause long-term consequences?
T2 = 30 min
What drug class is the initial therapy of choice in the first 5-20 min of a status epilepticus seizure? List all first-line options and alternatives available in SG, if any.
BZDs
1) First-line:
- IM midazolam (10 mg for > 40 kg, 5 mg for 13 – 40 kg, single dose)
- IV lorazepam (0.1 mg/kg/dose, max 4 mg/dose, may repeat dose once)
- IV diazepam (0.15 – 0.2 mg/kg/dose, max 10mg/dose, may repeat dose once)
2) Other options:
- IV phenobarbital (15 mg/kg/dose, single dose)
- Rectal diazepam (0.2 – 0.5 mg/kg, max 20 mg/dose, single dose)
- Intranasal midazolam, buccal midazolam
What drugs can be used as second-line options during the second therapy phase (i.e. 20-40 min in) of a status epilepticus seizure?
List all second-line options and alternatives available in SG, if any.
1) Second-line:
- IV phenytoin (20 mg PE/kg, max 1500 mg PE/dose, single dose)
- IV valproic acid (40 mg/kg, max 3000 mg/dose, single dose)
- IV levetiracetam (60 mg/kg, max 4500 mg/dose, single dose)
2) Other options:
- IV phenobarbital (15 mg/kg, max dose)
What drugs can be used as third-line options during the third therapy phase (i.e. 40-60 min in) of a status epilepticus seizure?
Repeat second-line therapy or anaesthetic doses of either thiopental, midazolam, pentobarbital, or propofol (all with continuous EEG monitoring)
Second-line:
- IV phenytoin (20 mg PE/kg, max 1500 mg PE/dose, single dose)
- IV valproic acid (40 mg/kg, max 3000 mg/dose, single dose)
- IV levetiracetam (60 mg/kg, max 4500 mg/dose, single dose)
